Ultrasound-promoted regioselective synthesis of 1-aryl-5-amino-1H- tetrazoles

Article abstract of DOI:10.1055/s-0032-1317513

A new method for the regioselective synthesis of 1-aryl-5-amino-1H- tetrazoles has been developed by the reaction of arylcyanamides with sodium azide using ZnClunder ultrasound irradiation in excellent yields. Copyright

Full text of DOI:10.1055/s-0032-1317513

LETTER
▌2795
lUettlertrasound-Promoted Regioselective Synthesis of 1-Aryl-5-amino-1H-tetra-
zoles
Regioselective Synthesis of 1-Aryl-5-amino
a
-1H-tetrazoles
b
a
c
Davood Habibi,* Mahmoud Nasrollahzadeh, Hesam Sahebekhtiari, S. Mohammad Sajadi
a
Department of Organic Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan 6517838683, Iran
Department of Chemistry, Faculty of Science, University of Qom, PO Box 37185-359, Iran
b
c
Department of Petroleum Geoscience, Faculty of Science, Soran University, PO Box 624, Soran, Kurdistan Regional Government, Iraq
Received: 24.08.2012; Accepted after revision: 05.10.2012
To the best of our knowledge, ultrasound irradiation has
not been used in the synthesis of tetrazoles so far. Due to
our ongoing interest in heterocyclic chemistry and synthe-
Abstract: A new method for the regioselective synthesis of 1-aryl-
5-amino-1H-tetrazoles has been developed by the reaction of aryl-
cyanamides with sodium azide using ZnCl under ultrasound irradi-
2
16
we wish to
ation in excellent yields.
sis of the nitrogen-containing compounds,
report a novel method for the regioselective synthesis of
the 1-aryl-5-amino-1H-tetrazoles by reaction of aromatic
cyanamides with sodium azide in the presence of ZnCl2
under ultrasound irradiation (Scheme 1).
Key words: 1-aryl-5-amino-1H-tetrazole, cyanamide, sodium
azide, ZnCl , sonochemical switching
2
Aminotetrazoles are important heterocyclic compounds
1
Ar
from a biological point of view. It is known that they
N
NH
N
H
N
Ar
C
N
ZnCl2, H2O
N
Ar
2
have applications in the pharmaceutical arena, as anticor-
NH2
+
N
+
N
))))), 70–80 °C
H
N
rosive additives, as explosive and information recording
NaN3
N
N
3
4
systems, as ligands, and also as precursors to a variety of
sole product
0%
5
nitrogen-containing compounds. Aminotetrazoles have
been reported as antiallergic and antiasthmatic, antiviral
and anti-inflammatory, antineoplastic, and to have cog-
nition disorder activities. For the synthesis of 1-substitut-
6
Scheme 1
7
8
9
ZnCl in H O catalyzed the reaction of 4-nitrophenylcy-
2
2
ed 5-amino-1H-tetrazoles, various methods have been
reported including alkylation of 5-aminotetrazole with al-
kyl halides (which results in mixtures of isomers in very
low yields),2 mercury(II)-promoted attack of an azide
anamide with sodium azide under ultrasonic irradiation,
and 1-(4-nitrophenyl)-5-amino-1H-tetrazole was the sole
product (Table 1). To study the combined effects of tem-
perature and reaction times, additional experiments were
performed in 40 °C, 60 °C, and 70–80 °C. The results
shown in Table 1 clearly indicate that increasing the tem-
perature and reaction time increases the yield.
,10
1
1
anion on a thiourea, addition of a primary amine to cy-
1
2
anogen azide, addition of hydrazoic acid to cyanamides
which often results in mixtures of 5-arylamino-1H-tetra-
(
1
3
zole and 1-aryl-5-amino-1H-tetrazole isomers), decom-
position of 1-aryltetrazoles at –70 °C,14 and a three-step Table 1 The Model Reaction at Different Temperatures and Reac-
tion Times under Ultrasound Irradiationa
synthesis from aromatic amines via isolation of cyana-
mide intermediates in low yields in which N-arylureas and
Entry
Temp (°C)
Time (h)
Yield (%)b
other byproducts were mostly formed.15 However, most
of these synthetic methods suffer from different draw-
backs such as employing toxic and volatile reagents such
as hydrazoic acid and cyanogen bromide, harsh reaction
conditions, complex catalysts or reagents, tedious isola-
tion procedures, low yields, and formation of mixtures of
isomers.
r.t.c
1
2
3
4
5
5
30
41
52
63
79
40
60
5
70–80
70–80
8
5
15
Therefore, it is desirable to develop more efficient and
convenient methods for the regioselective synthesis of 1-
substituted 5-amino-1H-tetrazoles without the application
a
Reaction conditions: 4-nitrophenylcyanamide (2 mmol), sodium
azide (3 mmol), ZnCl (2 mmol), H O (16 mL), 50 W, irradiation fre-
2
2
of hazardous reagents such as hydrazoic acid and cyano- quency 28 kHz (PARSONIC 2600s ultrasound cleaner).
b
gen bromide.
Isolated yield.
Room temperature.
c
SYNLETT 2012, 23, 2795–2798
Advanced online publication: 09.11.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317513; Art ID: ST-2012-D0710-L
Georg Thieme Verlag Stuttgart · New York
©

2796
D. Habibi et al.
LETTER
1
The H NMR spectrum of the product showed one peak at Table 2 Formation of 1-Aryl-5-amino-1H-tetrazoles via Secondary
Arylcyanamides (continued)
δ = 7.19 ppm indicative of the NH functional group and
2
confirmed the formation of 1-(4-nitrophenyl)-5-amino-
1
Entry Cyanamide
Product
Yield
(
H-tetrazole.1
6b,f
%)a
To study the effects of the nature of the substituents on the
benzene ring of the cyanamide, various 1-aryl-5-amino-
H2N
Me
Me
N
N
1H-tetrazoles were synthesized from different aromatic
N
CN
8
N
77
79
N
cyanamides containing both electron-releasing and elec-
tron-withdrawing groups with sodium azide in the pres-
H
Me
Me
ence of ZnCl in high yields under ultrasound irradiation
2
H2N
N
(
Table 2). We showed that the nature of the substituent
MeO
N
N
had no effect on the reaction time and nature of the prod-
uct which is in contrast with our previous reports for the
synthesis of aminotetrazoles using Lewis acids.1
N
9
N
CN
N
H
6a,b,f,g,j,k
MeO
MeO
H2N
Table 2 Formation of 1-Aryl-5-amino-1H-tetrazoles via Secondary
Arylcyanamides
N
MeO
OMe
CN
1
0
N
76
N
Entry Cyanamide
Product
Yield
%)a
N
H
(
OMe
N
N
N
H2N
CN
N
HN
O2N
2
H N
N
N
N
11
78
80
1
79
CN
N
N
H
O2N
Cl
Cl
H
NH2
N
H2N
N
N
Cl
NC
N
12
N
N
N
N
2
N
76
75
74
73
75
76
CN
CN
N
N
Cl
N
H
N
N
H
N
NH2
H2N
a
Yields are after workup.
N
Br
N
N
3
N
Under the same conditions but in the absence of sonica-
tion, the products are 1-aryl-5-amino-1H-tetrazoles or 5-
arylamino-1H-tetrazoles depending on the nature of the
CN
CN
CN
N
H
Br
Cl
1
6f
H2N
H2N
substituents (Scheme 2).
Cl
N
N
N
N
4
N
Ar
N
H
N
NH2
N
Ar
N
H
Ar
C
N N
N
N
ZnCl2, H2O
reflux
ZnCl2, H2O
NH2
N
N
Me
+
or
NH
N
))))), 70–80 °C
N
N
N
NaN3
N
N
5
N
N
Ar
sole product
H
N
N
H
Me
H2N
Scheme 2
Me
N
N
6
N
CN
As shown in Table 2, in contrast with previously reported
N
H
13
16b
16g
methods using HN3, AcOH, and FeCl –SiO
in
3
2
Me
H2N
which a mixture of isomers was obtained, in our method,
product formation was completely regioselective and
solely 1-aryl-5-amino-1H-tetrazoles were obtained.
N
Me
Me
N
N
7
N
CN
N
H
Interestingly, 4-nitrophenylcyanamide afforded 1-(4-ni-
trophenyl)-5-amino-1H-tetrazole (B, Table 2, entry 1),
whereas by application of various Lewis acids, 5-(4-nitro-
phenyl)amino-1H-tetrazole (A) was obtained (Scheme 3).
This result is in concordance with the synthesis of 1-(4-ni-
Me
Me
1
3
trophenyl)-5-amino-1H-tetrazole using hydrazoic acid
Synlett 2012, 23, 2795–2798
© Georg Thieme Verlag Stuttgart · New York

LETTER
Regioselective Synthesis of 1-Aryl-5-amino-1H-tetrazoles
2797
B
FeCl3–SiO2
NO2
))))), 70–80 °C
A + B
A/B = 1.8)
(
DMF, 110 °C
ZnCl2, H2O
reflux
A
B
A + B
B/A = 4.6)
glacial HOAc
r.t.
(
HN3
NHCN
EtOH, xylene, reflux
natrolite zeolite
DMF, 110–115 °C
A
+
ZnCl –AlCl –silica (ZAS)
2
3
A
NaN3
DMF, 120 °C
NH2
O2N
N
HN
N
N
N
O2N
N
N
N
H
N
A
B
Scheme 3
N
ZnCl2
+
N
N
N–
N
N–
Ar
NH2
ZnCl2
))))
N
H+
C
+
N+
N–
Ar
C
N+
N
Ar
C
ZnCl2
)
N
N
N
N
N
N
NH
H
–
H
Ar
N
Scheme 4
or decomposition of 1-aryl- tetrazoles15 by consecutive words, 5-arylamino-1H-tetrazoles A are the thermody-
ring opening, azidation, and intramolecular cyclization.
namic products which form in acidic environments or
high temperatures via the guanidine azide intermediate
using tetrazole ring opening. Generally, acidic environ-
ments and high reaction temperatures result in tetrazole
ring opening and formation of 5-arylamino-1H-tetrazoles
In addition, 2,5-dichlorophenylcyanamide (Table 2, entry
2) gave 1-(2,5-dichlorophenyl)-5-amino-1H-tetrazole,
while with ZnCl , Natrolite zeolite, ZnCl /AlCl /SiO , 5-
2
2
3
2
(2,5-dichlorophenyl)amino-1H-tetrazole and with AcOH
1
3,16b,f,i,j
(A isomer).
This product is not depending on the
and FeCl –SiO , a mixture of isomers was obtained.
3
2
nature of the substituent in the present method. In con-
Compared to other procedures for the synthesis of 1-aryl-
-amino-1H-tetrazoles, the notable features of our method
16f
trast, under reflux conditions, it may be that ultrasound
5
irradiation does not promote tetrazole ring opening and
hence isomerization of 1-aryl-5-amino-1H-tetrazole (B,
the kinetic product) to 5-arylamino-1H-tetrazole (A, the
thermodynamic product, Scheme 5).
are: (1) The reaction system is simple; (2) organic sol-
vents are not needed; (3) HN , Brønsted acid, and organ-
3
olithium reagents are not needed; (4) the yields of the
products are high; (5) high reaction temperature and pres-
sure are avoided; and (6) this method does not require col-
umn chromatography for the purification of products.
R
NH2
NH
C
N
NH
N
N
N
NH2
R
R
reflux
no )))))
R
C
The mechanism of the reaction may originate from the ni-
N
N
N
N3
N
N
N3
H
H
N
trile group coordinating with ZnCl and enhance its reac-
2
tivity with sodium azide (Scheme 4) to yield a guanidine
azide intermediate. However, the effect of ultrasound is
not clear in this case, and further experiments are neces-
sary to gain a clearer insight into these reactions. Herbst
and Garbrecht have shown that cyanamides may be con-
verted into aminotetrazoles using hydrazoic acid via the
B isomer
A isomer
Scheme 5
In conclusion, we have developed an efficient and simple
procedure for the synthesis of 1-aryl-5-amino-1H-tetra-
zoles under ultrasound irradiation. The applied procedure
is regioselective and has the advantages of excellent
yields, simple methodology, easy workup, and elimina-
tion of hazardous hydrazoic acid and cyanogen bromide.
guanidine azide intermediate which often result in a mix-
ture of isomers A and B, however.13
The 5-monosubstituted amino-1H-tetrazoles were synthe-
sized before by thermal isomerization of 1-substituted 5-
amino-1H-tetrazoles in boiling ethylene or melt state
1
7
(
180–200 °C). Furthermore, we have recently published
General Experimental Procedure for the Synthesis of 1-Aryl-5-
an efficient synthesis of 5-arylamino-1H-tetrazoles in
amino-1H-tetrazoles
high yields from the corresponding cyanamides via isom- A mixture of the appropriate arylcyanamide (2 mmol), NaN (3
3
mmol), and ZnCl (2 mmol) in H O (16 mL) was ultrasonicated for
erization of 1-aryl-5-amino-1H-tetrazoles over extended
2
2
reaction times (ca. 20 h) in DMF at 120 °C.16j In other
15 h at 70–80 °C. The reaction mixture was cooled to 25 °C, the sol-
id residue was filtered, washed with H O and treated with 3 M HCl
2
©
Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2795–2798

2798
D. Habibi et al.
LETTER
(
4 mL). Crystallization was peformed using aq EtOH to give the de-
Kozlov, A. S.; Lisker, I. S. Russ. J. Appl. Chem. 2003, 76,
572.
sired pure products.
(
4) Friedrich, M.; Galvez-Ruiz, J. C.; Klapötke, T. M.; Mayer,
The physical data (mp, IR, NMR) of known compounds were found
1
6a,d,f,j
P.; Weber, B.; Weigand, J. Inorg. Chem. 2005, 44, 8044.
to be identical with those reported in the literature.
Elemental
1
13
(5) Modarresi-Alam, A. R.; Khamooshi, F.; Rostamizadeh, M.;
Keykha, H.; Nasrollahzadeh, M.; Bijanzadeh, H. R.;
Kleinpeter, E. J. Mol. Struct. 2007, 841, 67.
analyses (CHN), IR, H NMR, and C NMR data of the novel tet-
razoles (Table 2, entries 1, 2, and 8) are given as below.
1
-(4-Nitrophenyl)-5-amino-1H-tetrazole (Table 2, Entry 1)
(6) (a) Connor, D. T.; Unangst, P. C.; Weikert, R. J. EP 279466,
1988; Chem. Abstr. 1988, 109, 231035. (b) Peet, N. P.;
Baugh, L. E.; Sundler, S.; Lewis, J. E.; Matthews, E. H.;
Olberding, E. L.; Shah, D. N. J. Med. Chem. 1986, 29, 2403.
1
7b
White color; yield 79%; mp 187–188 °C (lit. 185–187 °C). IR
KBr): 3390, 3290, 3230, 3125, 3010, 2860, 1647, 1608, 1592,
(
1573, 1520, 1510, 1464, 1415, 1381, 1344, 1312, 1291, 1180, 1127,
1105, 1071, 1033, 1009, 992, 863, 747, 732, 689, 555, 525, 505, 458
(
7) Girijavallabhan, V. M.; Pinto, P. A.; Ganguly, A. K.;
–1 1
cm . H NMR (500 MHz, DMSO-d ): δ = 8.43 (d, J = 7.2 Hz, 2 H),
6
Versace, R. W. EP 274867, 1988; Chem. Abstr. 1989, 110,
1
3
7.91 (d, J = 7.2 Hz, 2 H), 7.19 (s, 2 H). C NMR (125 MHz, DMSO-
2
3890.
d6): δ = 154.9, 147.1, 138.6, 125.3, 124.6. Anal. Calcd for
C H N O : C, 40.78; H, 2.93; N, 40.77. Found: C, 40.88; H, 3.01;
N, 40.67.
(8) Taveras, A. G.; Mallams, A. K.; Afonso, A. WO 9811093,
7
6
6
2
1998; Chem. Abstr. 1998, 128, 230253
(9) Mitch, C. H.; Quimby, S. J. WO 9851312, 1998; Chem.
Abstr. 1998, 130, 13997.
10) (a) Henry, R. A.; Finnegan, W. G. J. Am. Chem. Soc. 1954,
1
-(2,5-Dichlorophenyl)-5-amino-1H-tetrazole (Table 2, Entry 2)
(
White color; yield 76%; mp 260–262 °C. IR (KBr): 3325, 3170,
7
6, 926. (b) Finnegan, W. G.; Henry, R. A. J. Org. Chem.
3
1
5
3
1
095, 2900, 2820, 1648, 1576, 1481, 1450, 1394, 1301, 1251, 1136,
093, 1073, 1024, 983, 878, 821, 817, 754, 730, 698, 678, 660, 584,
10, 498 cm . H NMR (500 MHz, DMSO-d ): δ = 7.90–7.72 (m,
1
959, 24, 1565. (c) Barmin, M. I.; Gromova, S. A.;
–
1
1
Mel’nikov, V. V. Russ. J. Appl. Chem. 2001, 74, 1156.
(11) Batey, R. A.; Powell, D. A. Org. Lett. 2000, 2, 3237.
12) Joo, Y. H.; Shreeve, J. M. Org. Lett. 2008, 10, 4665.
13) Garbrecht, W. L.; Herbst, R. M. J. Org. Chem. 1953, 18,
6
H), 6.97 (s, 2 H). 13C NMR (125 MHz, DMSO-d ): δ = 155.7,
6
(
(
32.5, 132.2, 131.8, 131.7, 130.3, 130.0. Anal. Calcd for
C H N Cl : C, 36.52; H, 2.17; N, 30.43. Found: C, 36.64; H, 2.20;
N, 30.54.
7
5
5
2
1
014.
(
14) Congreve, M. S. Synlett 1996, 359.
1
-(2,6-Dimethylphenyl)-5-amino-1H-tetrazole (Table 2, Entry
(15) Vorobiey, A. N.; Gaponik, P. N.; Petrov, P. T.; Ivashkevich,
8)
O. A. Synthesis 2006, 1307.
White color; yield 77%; mp 147–149 °C. IR (KBr): 3430, 3295,
(
16) (a) Nasrollahzadeh, M.; Habibi, D.; Shahkarami, Z.; Bayat,
Y. Tetrahedron 2009, 65, 10715. (b) Modarresi-Alam, A.
R.; Nasrollahzadeh, M. Turk. J. Chem. 2009, 33, 267.
3
1
5
5
1
5
070, 2955, 2915, 2850, 1650, 1601, 1586, 1538, 1474, 1440, 1376,
349, 1260, 1217, 1160, 1114, 917, 869, 760, 700, 662, 636, 546,
16, 496 cm ; H NMR (500 MHz, DMSO-d ): δ = 7.03 (s, 3 H),
.24 (s, 2 H), 2.25 (s, 6 H). C NMR (125 MHz, DMSO-d ): δ =
57.5, 137.1, 136.6, 128.3, 126.3, 18.6. Anal. Calcd for C H N : C,
7.12; H, 5.86; N, 37.02. Found: C, 57.18; H, 5.90; N, 37.09.
–
1 1
6
(c) Kamali, T. A.; Habibi, D.; Nasrollahzadeh, M. Synlett
1
3
6
2
009, 2601. (d) Kamali, T. A.; Bakherad, M.;
9
11
5
Nasrollahzadeh, M.; Farhangi, S.; Habibi, D. Tetrahedron
Lett. 2009, 50, 5459. (e) Nasrollahzadeh, M.; Bayat, Y.;
Habibi, D.; Moshaee, S. Tetrahedron Lett. 2009, 50, 4435.
(
f) Habibi, D.; Nasrollahzadeh, M.; Faraji, A. R.; Bayat, Y.
Acknowledgment
Tetrahedron 2010, 66, 3866. (g) Habibi, D.;
We gratefully acknowledge the Bu-Ali Sina University for the sup-
port of this work.
Nasrollahzadeh, M. Synth. Commun. 2010, 40, 3159.
(h) Mohammadi, B.; Hosseini Jamkarani, S. M.; Kamali, T.
A.; Nasrollahzadeh, M.; Mohajeri, A. Turk. J. Chem. 2010,
3
4, 613. (i) Habibi, D.; Nasrollahzadeh, M.; Kamali, T. A.
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Synlett 2012, 23, 2795–2798
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